Phenyl-alkanolamine,alkylamine and alpha-aminoalkyl ketone derivatives as heart stimulants

ABSTRACT

NOVEL SUBSTITUTED 1-PHENYL-2-ALKYLAMINO-ALKANOLS, 1PHENYL-2-ALKYLAMINO-ALKANES AND A-AMINOALKYL PHENYL KETONES USEFUL AS HEART STIMULANTS ARE DISCLOSED.

United States Patent Claims-priority, application Great Britain, July18, 1970,

34,931/70 I v Int. Cl. C07c 127/16 US. Cl. 260-50117 1 Claim ABSTRACT OFTHE DISCLOSURE Novel substituted 1-phenyl-2-alkylamino-alkanols, 1-phenyl-2-alkylamino-a1kanes and a-aminoalkyl phenyl ketones useful asheart stimulants are disclosed.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION The compounds ofthe invention are those having the general formula:

Y B4 R (IJHN. bmouamx- IE. (I)

wherein R and R are each hyrogen or hydroxy with the proviso that atleast one is hydroxy; R is hydrogen, alkyl of from 1 to 4 carbon atomsor alkoxy of from 1 to 4 carbon atoms; R is acylamino,alkoxycarbonylamino of from 1 to '4 carbon atoms, amoyl or ureido, anyone of which may be separated from the phenyl ring by a methylene orethylene group; R R and R are each hydrogen or alkyl of from 1 to 4carbon atoms;

X is oxygen, sulfur, imino or a direct link; Y is hydrogen and hydroxy,two hydrogens or oxygen; n is If to '3 whenX is other than a direct linkandis 0 to 4 when X is a direct link; and the carboxylic acid esters andaldehyde condensation products of such a compound and thepharmaceutically-acceptable acid addition salts. In this specificationhalogen comprises fluorine, chlorine, bromine and iodine; imino groupindicates the group NR where R represents hydrogen or a lower alkylgroup; and'the term lower used to qualify an alkyl or alkoxy group,indicates that such group contains up to 4 carbon atoms.

3,816,516 Patented June 11, 1974 The aldehyde condensation products ofthe compounds of the invention are oxazolidines, having the formula:

which are formed by condensation of compounds of the invention in whichR is hydrogen and Y represents a hydrogen atom and a hydroxy group withan aldehyde of the formula R CHO, where R is hydrogen or a lower alkylgroup.

DETAILED DESCRIPTION OF THE INVENTION In the above formulae, when R isamoyl, it may be a carbamoyl or sulfamoyl group having the formula C s mor SO -NR R respectively, where R and R are each hydrogen or a loweralkyl or an aryl group or, together with the nitrogen atom to which theyare attached, form a heterocyclic group, e.g. a pyrrolidino, piperidino,piperazino or morpholino group. When such a group is separated from thephenyl ring by a methylene or ethylene group, R has the formula CH CONRR When R is an acylamino group, it may be derived from the amide of acarboxylic or sulfonic acid, i.e. it may have the formula R R N- where Ris an acyl group derived from either a carboxylic or a sulfonic acid, Ris hydrogen or a lower alkyl group, or R and R together with thenitrogen atom from a cyclic imido group. Moreover any such group may beseparated from the phenyl ring by a methylene or ethylene group, inwhich case R will have the fomula R R NCH or R R NCH CH Thus R may be,for example, a formamido, acetamido, propionamido, acrylamido,cycle-hexane carbonamido, benzamido, furmamido, phenyl acetamido,methane sulfonamido, benzene sulfonamido group, or a substitutedderivative thereof, e.g. a chloroacetamido, trifluoracetamido,glycolamido, phenoxyacetamido, toluarnido, nitrobenzamido,chlorobenzarnido or toluene sulfonamido group, or a correspondingamido-methyl or Z-amido-ethyl group, e.g. an acetamido-methyl orZ-acetamido-ethyl group. When R 'R N-- is a cyclic imido group, it maybe derived from an aliphatic or aromatic dicarboxylic acid; thus R maybe, for example, a succinimido, maleimido or phthalimido group or acorresponding imidomethyl or 2-imido-ethyl group.

When R is a uredio group, it may be uredio substituted with, one or morelower alkyl groups on one or both of the nitrogen atoms. Thus it may be,for example, a S-methyl ureido group.

Acids from which pharmaceutically acceptable addition addition salts ofthe compounds of the invention can be prepared are those which formnon-toxic addition salts containing pharmaceutically-acceptable anions,such as the hydrochloride, hydrobromide, hydroiodide, sulfate orbisulfate, phosphate or acid phosphate, acetate, maleate,

fumarate, lactate, tartrate, citrate, gluconate, saccharate,

and p-toulene sulfonate salts.

The compounds of the invention may be prepared in a number of ways:

(1) An amine of the formula:

HO R

R H HNHi is reacted with an aldehyde or ketone of the formula:

R (IV) where Z is halogen and R and R each represent hydrogen or, agroup PO, where P is an easily hydrogenolyzable protecting group, e.g. abeuzyl group, at least one of R and R being a group PO, is reacted withan amine of the formula:

UK (CH1) n (SHNHP R! to give a compound of the formula:

B4 R5 R1 R1 0 o oHNdmormnx To obtain a compound of the invention inwhich Y represents a hydrogen atom and a hydroxy group and R representshydrogen, the 'ketonic compound is reduced to the correspondingsecondary alcohol and the protecting groups (P) are removed byhydrogenolysis using a catalyst, e.g. palladium. To produce a compoundof the invention in which Y represents an oxygen atom and R representshydrogen, the'ketonic compound itself is freed of the protecting groups(P) by hydrogenolysis. The methods of isolation and purification aresimilar to those given for method (1). Y

(3) An amine ofthe formula:

- in which R, R and P are as defined in (2) ,above, is

reacted with a halo-compound of the formula:

Ra (IX) in which Z is halogen, to give a compound of the formula:

cmonun in which the single hydroxy-group is in either the 3- or the4-position, is reacted with a halo-compound of the formula (IX) to givea compound of the formula:

The methods of isolation and purification are similar to those given formethod (1). Where R is hydrogen, an excess amount of the amine is usedto prevent excessive formation of the tertiary amine by-product notrequired.

(5) The compounds of the invention in which R represents an acylamino, alower alkoxy carbonylamino or a ureido group attached directly to thephenyl ring, i.e. groups wherein the free valency is on the nitrogenatom, R represents a hydrogen atom, and Y represents a hydr0 gen atomand a hydroxy group or an oxygen atom, may be prepared from a phenacylhalide of the formula (V) as defined in method (2) and an amine of theformula:

xrr

X(CH2),,CH NHP OnN (XIII) to give a compound of the formula: I

- R R I R CQ(JHN(JH(CH2):=X I

' N01 (XIV) For the preparation of compounds wherein Y represents ahydrogen atom and a hydroxy group, the ketonic cornpound'is' thenreduced tothe corresponding secondary alcohol, whereas for thepreparation of compounds wherein Y represents an oxygen atom, this stageis omitted, The nitro group is reduced by hydrogenation in 5, the'pre'sence of a ca'talyst, e.g., Raney nickel, to an amino group togive-a compound of the formula:

CHI]ICH(CH;),,X

N H: (XV) in which Y represents a hydrogen atom and a hydroxy group oran oxygen atom. The compound (XV) is then reacted with a suitablereagent for conversion of the amino group to an acylamino group, a loweralkoxycarbonylamino group or a ureido group; e.g. for conversion of theamino group to a formamido, ethoxycarbonylamino or a 3-methyl-ureidogroup, suitable reagents are formic acid, ethyl chloroformate andmethylisocyanate respectively. Finally, the protecting groups (P) areremoved by hydrogenolysis using a catalyst, e.g. palladium, togiveacompound of the formula (I) wherein R representsan acylamino, a,lower alkoxycarbonylamino or a ureido group attached directly to thephenyl ring, and Y represents a hydrogen atom and a hydroxy group or anoxygen atom.

(6) The compounds of the invention in which R represents an acylarnino,a lower alkoxycarbonylamino or a ureido group attached directly to thephenyl ring, and Y represents two hydrogen atoms, may be prepared froman amine of the formula (VIII) as defined in method (3) and ahalo-compound of the formula:

is then reduced hydrogenation in the presence 'of-a catalyst, e.g.LRaney nickel, to an amino gr to 'givea compound of the formula:

4 5 R2 "1 |v J1 CH HNCHQHzhX NH: (XVIII) The ompourid ;(XVIl;I) is thenreacted with a suitable re'agent' fo'r conversion of the amino group toan acylamino," a lower alkoxycarbonylamino or a ureido group such as areexemplified in method (5). Finally, the protecting groups (P) areremoved byhydrogenolysis using a catalyst, e.g. palladium.

(7) The compounds of the invention in which R represeats a lower alkylgroup may be prepared by the methods (3 ),(5) and 6) 'bu't withlth eprotecting groups ('P) cfi'ito 'the nitrogen 'atoinin the startingmaterials VIII), (XIII) an (VIII) respectively, replaced .3 I (8) -Thealdehyde condensation products of the compounds of the invention may beprepared by reactinga compound of the inventi'orfin widens and R areeach hydrogen with an aldehyde ofgtheformula 'R CHO,'Where R is hydrogenor a lower alkyl group, in a diluent or solvent, e.g. ethanol,preferablyiiin the presence of an acid catalyst, e.g. hydrochloric oracetic acid, and preferably at an elevated temperature. The water formedin the reaction may be removed by azeotropic distillation by means of anentraining solvent, e.g. benzene, or by dehydrating agent, e.g.anhydrous potassium carbonate.

In the general methods (5) to (8), the methods of isolation andpurification are similar to those given for method (1).

Those compounds of the invention in which Y represents a hydrogen atomand a hydroxy group exist in D- and L-optically active isomeric formsand the invention includes these forms as well as the racemic mixtures.Method (1) described above may be used to prepare the optically activeisomers by using the appropriately substitued phenyl-ethanolamineenantiomer as starting material, whereas methods (2) and (5) applied tosuch compounds of the invention -will result in the production of aracemic mixture. Alternatively, the racemic product of each of the abovemethods may be resolved by well-known techniques, e.g. by fractionalcrystallization of an addition salt formed with an optically activeacid.

Compounds in which R and/or R are other than hydrogen have more than oneasymmetric center and exist as two or more racemic pairs ofdiastereoisomers. In general, the products of the above methods will bea mixture of the pairs of stereoisomers, and these pairs may usually beseparated from each other by physical methods, e.g. by fractionalcrystallization or chromatography of the free bases or suitable salts.The invention includes the separated pairs, as well as mixtures thereof,as racemic mixtures or as separated D- and L-forms.

The activity of compounds of the invention as fi-adre nergic stimulantsfor the heart has been shown by their effectiveness in one or more ofthe following tests: (a). increasing the force of contraction of theisolated electrically driven guinea pig left atrium, and of isolatedelectrically driven cat papillary muscle; (b) increasing the forceand/or rate of contraction of spontaneously beating guinea pig atria;(c) increasing cardiac output in the anaesthetized cat with an implantedleft ventricular catheter; (d) increasing cardiac output in theconscious dog with an implanted left ventricular catheter.

In test (a), the increased contractility of the muscle in response tothe test compound is measured in two animal species (guinea pig andcat). The experiments are then repeated in the presence of a p-receptorblocking agent and on reserpinized atria to determine whether the testcompound is a directly acting fi-receptor agonist;

In test (b) any selective action of compounds of the invention is showncompared with the catecholamines, noradrenaline and adrenaline, i.e.whether or not they increase the force of atrial contraction to agreater extent than the rate.

In test (c) the inotropic action of the test compounds followingintravenous administration is measured in the anaesthetized cat. Theperipheral effects of the compounds (e.g. effect on blood pressure) arealso measured in this preparation.

In test (d) the inotropic action of the test compound following oraladministration to a dog with an implanted left ventricular catheter ismeasured.

By virtue of their performance in tests (a) to (d), the preferredcompounds are to be found generally in those compounds of the inventionin which R represents hydrogen, R represents a hydroxy group, Rrepresents hydro 1-(4-hydroxyphenyl)ethanol hydrochloride show goodpotency of activity in test (a), but are inferior to the threeparticularly preferred compounds in test The compounds of the inventioncan be administered alone, but will generally be administered inadmixture with a pharmaceutical carrier selected with regard to theintended route of administration and standard pharmaceutical practice.For example, they may be administered orally in the form of tabletscontaining such excipients as starch or lactose, or in capsules eitheralone or in admixture with excipients, or in the form of elixirs orsuspensions containing flavoring or coloring agents. They may beinjected parenterally, for example, intramuscularly or subceutaneously.For parenteral administration, they are best used in the form of asterile aqueous solution which may contain other solutes, for example,enough salts or glucose to make the solution isotonic.

In general, the compounds of the invention are administered in dosagesof from about 0.5 to about 20 mg./ per kg. of body weight per day takenorally in three of four divided doses. Dosages for intravenousadministration are about one-tenth of the above dose in a single doseper day.

EXAMPLE I A mixture of DL-octopamine (4.6 g.), 4-carbamoylphenoxyacetone (5.8 g.) and ethanol (150 ml.) was boiled under reflux for 8hours in the presence of molecular sieves, then hydrogenated overplatinum oxide at 50 p.s.i. and 50 C. Filtration and evaporation invacuo of the filtrate gave a viscous oil which was triturated with etherto provide a semi-solid material. This material was then triturated withethanol and the residual white solid crystallized from aqueousdimethylformamide to afford DL-2- [2-(4-carbamoyl-phenoxy)-1-methylethylamino]-1- (4 hydroxyphenyl)ethanolhemihydrate (2.0 g.), M.P. 195-198" C.

Analysis.Calcd. for C H N O -H O (percent): C, 63.70; H, 6.83; H, 8.26.Found (percent): C, 63.84; H, 6.37; N, 8.27.

EXAMPLE H Also prepared by the method described in Example I fromDL-octopamine and 2-carbamoyl-4-methylphenoxy acetone wasDL-2-[2-(2-carbamoyl-4-methylphenoxy)-1-methylethylamino]-1-(4-hydroxyphenyl)ethanol, isolated as the oxalate,M.P. 1756 C.

Analysis.-Calcd. for C H N O -C H O (percent): C, 58.06; H, 6.03; N,6.45. Found (percent): C, 58.23; H, 6.43; N, 6.65.

EXAMPLE III A stirred mixture of 4-benzyloxyphenacyl bromide (18.3 g.),N-[2 (4 carbamoylmethylphenoxy)ethylbenzylamine (17.0 g.), anhydroussodium carbonate (6.4 g.) and ethanol (200 ml.) was boiled under refluxfor 1 hour, then allowed to cool and filtered. Evaporation in vacuo ofthe filtrate aflorded an oil which could not be induced to solidify. Itwas thus stirred with a mixture of sodium borohydride (2.4 g.), ethanol(100 ml.) and 1,4-dioxane (100 ml.) for 18 hours at room temperature.The resulting mixture was acidified with 50% aqueous acetic acid thenevaporated in vacuo to provide an oil which on trituration with aqueoussodium carbonate solution, gave a white powder (17.3 g.).Crystallization of a sample (2.0 g.) from methanol furnishedDL-2-[N-benzyl-2 (4 carbamoylmethylphenoxy)ethylamino]1-(4-benzyloxyphenyl)ethanol hydrate (0.9 g.) M.P. 105107 C.

Analysis.Calcd. for C H N O (percent): C, 72.70; H, 6.86; N, 5.30. Found(percent): C, 72.99; H, 6.86; N, 5.31.

The previous product (15.3 g.) was hydrogenated over 10%palladium/charcoal (1.5 g.) in 50% aqueous acetic acid solution (100ml.) in a Parr hydrogenator at p.s.i. and room temperature. Filtrationof the resulting mixture followed by evaporation in vacuo of thefiltrate gave an oil which was neutralized by addition of 10% aqueoussodium carbonate solution. The aqueous phase was decanted and theresidual oil treated with water in which it rapidly dissolved. Onstanding, the latter solution deposited a white solid; several morecrops were obtained by concentration of this solution, and also from thedecantate, to give a total yield of 6.9 g. Crystallization from methanolalTorded DL 2[2-(4-carbamoylmethylphenoxy)ethylarnino]l-(4-hydroxyphenyl)ethanol (4.1g.), M.P. 160- 161 C.

Analysis.-Calcd. for C H N O (percent): C, 65.44; H, 6.71; N, 8.48.Found (percent):'C, 65.85; H, 6.72; N, 8.36.

EXAMPLE IV (A) A stirred mixture of 3-benzyloxyphenacyl bromide 15.25g.), N-[2-(4-sulfamoylphenoxy)ethyl]benzylamine (15.3 g.), anhydroussodium carobnate (5.3 g.) and ethanol (200 ml.) was boiled under refluxfor 1 hour, then allowed to cool and filtered to remove the sediment ofinorganic salts. Evaporation in vacuo of the filtrate afforded a yellowsolid, which was distributed between water (500 l.) and chloroform (400ml.). The layers, which ini tially coalesced into an emulsion, wereclarified by filtration through an anhydrous sodium carbonate pad. Thechloroform layer was separated, dried over anhydrous magnesium sulfateand evaporated in vacuo to afiord a viscous yellow oil, which was foundto be very impure from thin layer chromatography evidence. Addition ofdi ethyl ether, chilling, evaporation of the solvent and standing atroom temperature eventually solidified the oil to a cake, which wascrushed, washed with diethyl ether and dried, providing a cream-coloredpowder, yield 15.9 g., M.P. 110-115 C.

(B) A solution of the crude product of (A) (13.25 g.) in 1:1 ethanol:1,4-dioxane (100 ml.) was added over one minute to a stirred suspensionof sodium borohydride (0.95 g.) in ethanol (100 m1.) at roomtemperature, and the mixture was stirred for a further 21 hours. Theresulting mixture was then acidified with glacial acetic acid, the wholethen being evaporated in. vacuo to a tarry material to which was addedaqueous sodium carbonate solution. Water was added, and the resultingsolution extracted with chloroform. The layers, which initiallycoalesced into an emulsion, were clarified by filtration throughdiatomaceous earth. The chloroform layer was separated, driedoveranhydrous magnesium sulfate and evaporated in vacuo to afford an oilwhich could not be induced to solidify despite trituration in 40-60 C.petrol ether and diethyl ether with chilling.

(C) The crude product of the previous stage (13.2 g.) was hydrogenatedover 10% palladium/charcoal (1.5 g.) in glacial acetic acid ml.) in aParr hydrogenator at 15 p.s.i. and room temperature. Filtration of theresulting mixture followed by evaporation in vacuo of the filtrate gavean oil which was dissolved in ethanol (200 ml.). To the ethanolicsolution was added concentrated hydrochloric acid which resulted inprecipitation of a white crystalline solid, which, after concentrationby evaporation of the suspension to a volume of 50 ml., was collected byfiltration and dried. It was then dissolved in a boilingethanol/methanol mixture, the solution filtered, and the filtratechilled and diluted with diethyl ether. The resultant precipitate ofwhite powder was collected by filtration and dried. The product,DL-2-[2-(4-sulfarnoy1- phenoxy)ethylamino] 1-(4-hydroxyphenyl)ethanolhydrochloride (5.95 g.) melted at 184 C. with decomposition.

Analysis.Calcd. for C H N O S-HCl (percent): C, 49.42; H, 5.44; N, 7.21.Found (percent): C, 49.33, H, 5.58; N, 7.14.

The following compounds have been prepared, using the method of ExamplesIII and IV, from the appropriate starting materials.

The compounds of Examples XV, XVI and XVII were produced according tothe method of Examples III and IV butomitting the'sodium borohydridereduction and effecting the hydrogenation of the carbonyl intermediateat a pressure of about 1000 p.s.i. and at room temperature in'thepresence of palladium/charcoal catalyst.

water and dried to aflord DLZ-[N-benZyI-Z-(t-carbamoylphenoxy)ethylamino] 1 (3,4 dibenzyloxyphenyl) ethanol (10.1g.), M.P. 110-1 C.

OH R R2 63H. Cfi.NH.CHaCH2 O Analysis percent (calcu ated in brackets) I5 Position Salt/freebase Enample a t R OfHO- M.P.,O. c H N H i-GONE; r14- Freebase, .56 6.27 8.86 V a 193F5 [64.54] 6.371 [8.86]

4-NHCOCHa I H. 4- Hydrochloride, 59.59 .47 7.39

p v 7, 213-6"! 59.921 [6. 621 [7.36] i-CQNH) ,CH; 4- Free base, 65.416.63 8.25 v 193-6"! [65.44] [6.71] [8.48]

4-NHCOCH; H 3- Hydroohlorlde 56 6.01 7.25

' sesquihydrate, [54 89] [6. 64] [7. 111 mes.

Ix fH enncoom H 4- Hydrochloride, 58.52 6.46 7.68

4-CH5CONH1 0H, 4- Free base, 66.34 7.21 7.88 f I 132-4". 66.261 7.02][8.13] j 1511000112011. 4- Hydrochloride, 59.68 6.59 7.31

".aioolsu'i' 4- Hydrochloride, 58. as 6. 4a 7. 77 ISO-2. [58.94] [6.32][7.64]

"ennsozom 4- Free base, 56.08 5.85 7.48 I 151-a. 55. 721 [6. 051 [7.64]2. 1 1300 on, 11 4- Acetate, 61. 77 6. 61 7. 14

i-C6173: CH: 4- Free base, 65.58 6. 74 8.28

qncoon'i cm 4- Free base, 66. 43 7.03 8.01

vi-orilcoisfil CH; 4 Freebase, 66.36 6.98 8.19 i a 162-43." 66.26] 7.021[8.13] xvnI.- ."H" ecuin'fioocn. H a- Free base, 66.13 7.66 7.84 I I1475-1485". [66.26] 7.02] [8.13]

llh ero isomers. I Erythro isomers.

EX A MPLE XIX ,A.mixture Iof 3,4-dibenzyloxyphenacyl bromide (8.2 g.)N-[Z (4 -v carbamoxylphenoxy)ethyl]benzylamine .4 g.), anhydrous sodiumcarbonate (2.1 g.) and ethanol 250 ml.) wasboiled under reflux for 3hours, then filtered hot to i-emove the inorganic sediment and cooled to0 C. The resultant precipitated solid was collected by filtration,washed with diethyl ether and dried. The product, N benzyl-N-(3,4dibenzyloxybenzoyl)methyl-2-(4- carbamoylphenoxy)ethylamine (11.0 g.)melted at 14( -2C. U I h .'4'nulysis. +Calcd. for C3 H N O -05H O(percent): C, 74.88; H, 6. 1; N, 4.60. FQund (percent) C, 75.83; H,5.87; N, 4.38.- I ,Stptlirir borohydride (4.0 g.) was dissolved in theminimum yolume of water and2 drops of 5N sodium hydroxide solution wereadded The solution was added to; afsuspension of the previous product(10.5 g.) in ethan ol (BOO-mil and the mixturestirred for 3 hours 'atroom temperature, then gently warmed on a steam bath to achievecomplete."solution,..and cooled again, stirring then being continued atroom temperature for a further The solution was acidifiedby additionof-a'few lacialj'ace'tidacid and the volume of the susp I it) reducedbyoiiefhalf.Water(300 ml.) was added and the' solid" collected filtration,washed in boiling Analysis.-Calcd. for C H N O 05H 0 (percent): C,74.60; H, 6.43; N, 4.58. Found (percent): C, 74.61; H, 5.80; N, 4.32.

The previous product (6.0 g.) was hydrogenated over 10%palladium/charcoal (600 mg.) in 50% aqueous acetic acid solution (60ml.) in a Parr hydrogenator at 15 p.s.i. and room temperature.Filtration of the resulting mixture followed by evaporation in vacuo ofthe filtrate at less than 40 C. gave a brown syrup. Addition of anisopropanol/methanol mixture gave a solution and a black solid. Thelatter was removed by filtration and to the filtrate was added etherealhydrogen chloride, which produced a gum. Decantation followed bytrituration of the gum in methanol afforded a pink solid A (0.4 g.). Thedecanted isopropanol/methanol/diethyl ether solution was concentrated byevaporation in vacuo, which resulted in precipitation of some morepink'solid B (1.3 g.). The filtrates from the collections of solids Aand B were combined and treated with a small volume of diethylether.Cooling of this solution at 0 produced a third cropof crystals, solid C(0.2 g.). Solids A, B and C were combined and dissolved in the minimumvolume of methanol,

'uct,collected by filtration and dried, consisted of DL-2 lf2-" 11(4-carbamoylphenoxy)ethylamino] 1 (3,4-dihydroxyphenyl)ethanolhydrochloride (1.05 g.), M.P. 184 C. with decomposition.

Analysis.Calcd. for C H N O -HCl (percent): C, 55.36; H, 5.74; N, 7.60.Found (percent): C, 54.98; H,

EXAMPLE XX A mixture of 3,4-dibenzyloxyphenacyl bromide (32.8 g.),N-[2-(4-acetamidophenoxy)ethyl]benzylamine (22.8 g.), anhydrous sodiumcarbonate (8.4 g.) and ethanol (1 liter) was boiled under reflux for 2hours, then filtered hot to remove the inorganic sediment and evaporatedin vacuo to aflord a thick syrup. The latter was dissolved in hotisopropanol and the solution cooled, the precipitated solid then beingcollected by filtration. To a hot solution of the solid in freshisopropanol were added a few milliliters of ethyl acetate, and thesolution was then allowed to cool to room temperature. The crystallizedsolid was collected by filtration, washed in diethyl ether and dried.Recrystallization from an isopropanol/ethyl acetate mixture afforded Nbenzyl-N-(3,4-dibenzyloxybenzoyl)methyl-2- (4acetamidophenoxy)ethylamine (32.8 g.), M.P.- 104- 6 C.

Analysis.-Calcd. for C H N O (percent): C, 76.20; H, 6.23; N, 4.56.Found (percent): C, 75.93; H, 6.28; N, 4.13.

Sodium borohydride (12.0 g.) was dissolved in water (40 ml.) and 8 dropsof 5 N sodium hydroxide solution were added. The solution was added to asuspension of the previous product (32.8 g.) in ethanol (800 ml.) andthe mixture gently warmed on a steam bath to achieve complete solution.After removal of the steam' bath, the solution was stirred for 10minutes and poured into water containing a little acetic acid, whichresulted in the precipitation of a gummy solid. The latter was extractedinto chloroform and the chloroform solution separated and evaporateddown in vacuo to give a syrup (20.4 g.), which consisted of crudeDL-2-[N-benzyl-2-(4-acetamidophenoxy) ethylamino] -1- (3 ,4-dibenzyloxyphenyl) ethanol.

The previous product (20.0 g.) was hydrogenated over 10%palladium/charcoal (2.0 g.) in 50% aqueous acetic acid solution (200ml.) in a Parr hydrogenator at p.s.i. and room temperature. Filtrationof the resulting mixture followed by evaporation in vacuo of thefiltrate at less than 40 C. gave a syrup, which was subsequently takenup into toluene and the solution evaporated down, this process beingrepeated until the residue consisted of a pink solid. The latter wasdissolved in hot methanol and isopropanol added to the solution. Afterremoval of excess methanol by evaporation in vacuo, a precipitateformed, and this was collected by filtration and dried (yield 11.2 g.;M.P. 150 C. with decomposition). Recrystallization from ethanol afforded7.1 g. of crystalline material, M.P. 165 C. with decomposition. Thefiltrate from the crystallization in isopropanol/methanol was treatedwith ethereal hydrogen chloride, which resulted in precipitation ofwhite crystals (4.6 g.) of DL-2-[2-(4-acetamidophenoxy)ethylamino]1-(3,4-dihydroxyphenyl)ethanol hydrochloride hemihydrate, M.P. 176 C.with decomposition.

Analysis.Calcd. for C H N O -HCl-(L5H O (percent): C, 55.16; H, 5.92; N,7.15. Found (percent): C, 55.27; H, 6.21; N, 6.88.

EXAMPLE XXI Also prepared by the method described in Examples XIX and XXfrom 3,4-dibenzyloxyphenacyl bromide and N-[2 (4 carbamoylmethylphenoxy)ethyl]benzylamine was DL 2-[2-(4-carbamoylmethylphenoxy)ethylamino]-1-(3,4-dihydroxyphenyl)ethanol hydrochloride, M.P. 224 8 C.

Aanalysis.-Calcd. for c1,I-I,,N,0,Hc1 (percent): C, 56.47; H, 6.05; N,7.32. Found (percent): C, 56.49, H, 6.04; N, 7.51.

12 EXAMPLE xXn A mixture 3,4-dibenzyloxyphenacyl bromide (32.8 g.), N-[2(4 carbamoylmethylphenoxy)ethyl]benzylamine (22.8 g.), anhydrous sodiumcarbonate (8.4 g.) and ethanol (1 liter) was boiled under reflux for 3hours, then filtered hot to remove the inorganic sediment and evaporatedin vacuo to aiford a thick syrup. The latter was crystallized upontrituration in diethyl ether and a sample of the resultant solid wasrecrystallized from ethanol to give N benzylN-(3,4-dibenzyloxybenzoyl)methyl-2-(4-carbamoylmethylphenoxy)ethylamine,M.P. 99-101 C.

Analysis.--Calcd. for C H N O5-05H O (percent): C, 75.10; H, 6.30; N,4.40. Found (percent): C, 75.42; H, 6.22; N, 4.17.

The previous product (7.0 g.) was hydrogenated over 10%palladium/charcoal (700 mg.) in 50% aqueous acetic acid solution (70ml.) in a Parr hydrogenator at 15 p.s.i. and room temperature.Filtration of the resulting mixture was followed by evaporation in vacuoof the filtrate to dryness, the crude product then beingazeotroped inturn with water and toluene. The resulting syrup was dissolved inmethanol, and ethereal hydrogen chloride was slowly added to themethanolic solution, yielding a precipitate of fawn crystals (4.0 g.)which were subsequently collected by filtration and recrystal lized fromwater with a little concentrated hydrochloric acid added. The crystalswere collected by filtration and dried to give2-(4-carbamoylmethyl-phenoxy)-N-(3,4- dihydroxybenzoyl)methyl ethylaminehydrochloride (3.0 g.), M.P. 240 C. with decomposition.

Analysis.Calcd. for C H N O -HCl (percent): C, 56.78; H, 5.55; N, 7.36.Found (percent): C, 57.01; H, 5.73; N, 7.22.

EXAMPLE XXHI Also prepared by the method described in Example XXII from3,4-dibenzyloxyphenacyl bromide and N-[2- 2-carbamoyl-4-methylphenoxy)-ethyl] benzylamine was 2-(2-carbamoyl-4-methylphenoxy) N(3,4-dihydroxybenzoyl)methyl ethylamine hydrochloride hemihydrate, M.P.C., with decomposition between 218223 C.

Analysis.-Calcd. for C H N O -I-ICl-0-5H O (percent): C, 55.44; H, 5.69;N, 7.19. Found (percent): C, 55.62; H, 5.62; N, 7.37.

EXAMPLE XXIV A mixture of N-2-(3,4-dibenzyloxyphenyl)ethyl benzylamine(13.6 g.), 2-(4-sulfamoylphenoxy)ethyl chloride (4.8 g.) and dry xylene(50 ml.) was boiled under reflux for 12 hours. The solution was cooledand the precipitated solid removed by filtration, the filtrate thenbeing evaporated in vacuo to dryness and taken up into diethyl ether.Insoluble material was removed from the ethereal solution by filtration,and the filtrate treated with ethereal hydrogen chloride, which resultedin the precipitation of a yellow solid. The latter was collected byfiltration and recrystallized from a methanol/isopropanol mixture givingN-[2-(3,4-dibenzyloxyphenyl)ethyl] N[2-(4-sulfamoylphenoxy)ethyl]benzylamine hydrochloride (5.8 g.), M.P.178-181 C.

Analysis.-Calcd. for C H N O S-HCl (percent) C, 67.40; H, 5.96; N, 4.25.Found (percent): C, 67.62; H, 6.03; N, 4.26.

The previous product (5.7 g.) was hydrogenated over 10%palladium/charcoal in glacial acetic acid in a Parr hydrogenator at 15p.s.i. and room temperature. The catalyst was removed by filtration andthe filtrate evaporated in vacuo to a gum, which was triturated in alittle acetone. The resulting grey solid was filtered off, andrecrystallized from 5 N hydrochloric acid givingN-[2-(3,4-dihydroxyphenyl) ethyl] -2- (4-sulfamoylphenoxy) ethylaminehydrochloride as pale mauve crystals, M.P. 245-7 C. I

Analysis.-Calcd. for C H N O S-HCl (percent): C, 49.40; H, 5.44; N,7.20. Found (percent): C, 49.39; H; 5.41; N, 7.31.

13 Iheiollowing .compounds have been prepared, using the method-ofExample from the appropriate starting materials.

14 Analysis.Calcd. for C H N O -HCl (percent): C, 60.62; H, 6.28; N,8.32. Found (percent): C, 60.41; H, 6.33; N, 8.56.

Analysis percent (calculated in brackets) R -11: Salt, M.P.,C. c H N XXV4CH: Z'CONHQ Hydrochloride 58.66 6.33 7.47 200-202. [58.93] [0.32][7.64]

xxvr H eo'oNH, "Hydrchlorlde 57.46 5.90 8.02

A mixture of N-2-(3,4-dibenzyloxyphenyl)ethyl benzylamine (1 2.0 g.),2-(4-acetamidophenoxy)ethyl chlw ride (3.1 g.) and dry dimethylformamideml.) was boiled under reflux for 10 hours. The solution was cooled, moredimethylformamide ml.) added, and the precipitated solid removed byfiltration. The filtrate was evaporated in vacuo to dryness and theresultant solid stirred in chloroform, after which undissolved materialwas removed by filtration and the filtrate was evaporated in vacuo todryness to give the crude product, N-[2-(3,4- dibenzyloxyphenyDethyl] N[2-(4-acetamidophenoxy) ethyl]benzylamine.

The previous product was hydrogenated over 10% palladium/charcoal inaqueous acetic acid with a few drops of concentrated hydrochloric acidadded in a Parr hydrogenator at 15 p.s.i. and room temperature. Thecatalyst was removed by filtration and the filtrate evaporated in vacuoto a gummy solid. The latter was crystallized from dilute hydrochloricacid, giving N-[2 (3,4-dihydroxyphenyDethyl] 2 (4acetamidophenoxy)ethylamine hydrochloride (2.5 g.), M.P. 219-221 C.

Analysis.Calcd. forC H N O 'HCl (percent): C, 58.93; H, 6.32; N, 7.64.Found (percent): C, 58.97; H, 6.26; N, 7.90.

The following compounds have been prepared, using the method of ExampleXXVII, from the appropriate starting materials.

EXAMPLE XXXIII (A) A stirred suspension of 4- benzyloxyphenacyl bromide(30.5 g.), N-benzyl-2-(4-nitrophenoxy)ethylamine hydrochloride (30.85g.) and anhydrous sodium carbonate (21.2 g.) in ethanol (300 ml.) wasboiled under reflux for 1 /2 hours. The mixture was then filtered Whilestill hot to remove sodium salts and the ethanolic filtrate evaporatedin vacuo to a brown oil (48.7 g.), consisting of crudeN-benzylN-(4-benzyloxybenzoyl)methyl-2-(4- nitrophenoxy) ethylamine.

(B) Addition of 1,4-dioxane (150 ml.) to the product of (A) causedprecipitation of some white solid. The latter was removed by filtration,and the dark brown filtrate added over 5 minutes to a stirred suspensionof sodium borohydride (3.8 g.) in ethanol (100 ml.) at room temperature.Stirring was continued for 20 hours, after which the mixture wasacidified with glacial acetic acid, diluted by addition of water andbasified with aque- HO- CHZCHZNHCHzCHgO- Analysis percent (calculated inbrackets) Example R R Salt, M.P., C. C H N XXVIIL- Z-OCH: 4-CONH1Hydrochloride 55. 6. 22 7. 09

0.25 hydrate [55. 82] [6. 05] [7. 23] 168-171".

XXIX H 3-CONH; Hydrochloride 57. 97 5. 92 7.79

XXX.---- H 4-CH CONH Hydrochloride 58. 83 6. 35 7. 45

EXAMPLE XXXI A mixture of 2-(4-hydroxyphenyl)ethylamine (5.6 g.),2-(4-carbamoylphenoxy)ethyl chloride (4.0 g.) and dimethylformamide (25ml.) was heated at C. for 4 hours. After cooling to room temperature,the mixture was poured into water and the resultant precipitated solidwas collected by filtration, 'washed in turn with water, acetone anddiethyl ether, and finally dried. The product,N-[2-(4-liydroxyphenyl)ethyl]-2-(4-carbamoylphenoxy)ethylarninehydrochloride melted with decomposition at 284 C.

5 ous sodium carbonate solution. The solution was extracted withchloroform (2X 200 ml.) and the chloroform solutions separated,combined, dried over anhydrous magnesium sulfate and evaporated in vacuoto a brown oil (41.8 g.), consisting of crude DL-2-[N-benzyl-2-(4-nitrophen oxy) ethylamino] -1- (4-b enzyloxyphenyl)ethanol.

(C) The crude product of (B), dissolved in a mixture of ethanol ml.) and1,4-dioxane (50 ml.), was submitted to hydrogenation at 50 p.s.i. androom temperature 75 in the presence of Raney nickel catalyst. Removal of15 catalyst by filtration followed by evaporation of the filtrate invacuo yielded crude DL-2-[N-benzyl-2-(4- aminophenoxy)ethylamino] 1 (4benzyloxyphenyl) ethanol (37.85 g.) as a dark brown tar.

(D) A solution of methyl isocyanate (2.85 g.) in chloroform (25 ml.) wasadded over /2 minute to a stirred solution of the product of (C) (23.4g.) in chloroform (100 ml.). Stirring at room temperature was continuedfor 2 /2 hours, after which the solution was evaporated in vacuo to abrown oil. A small sample of the latter yielded a white powder ontrituration in 40-60 petrol ether/diethyl ether/acetonitrile, and theremaining oil was triturated in 4060 petrol ether, the mixture beingseeded with the foregoing white powder to yield, on standing, a greysolid mass. The latter was crushed and dried, and consisted of crudeDL-2-[N-benzyl-2-(4-{3- methylureido}phenoxy)ethyl amino] 1(4-benzyloxyphenyl)ethanol. A small portion was crystallized fromacetonitrile to yield crystals, M.P. 1l3116 C.

Analysis.-Calcd. for C H N O (percent): C, 73.12; H, 6.71; N, 8.00.Found (percent): C, 72.82; H, 6.59; N, 8.01.

('E) The product of (D) (22.0 g.) dissolved in glacial acetic acid washydrogenated at 15 p.s.i. and room temperature in the presence ofpalladium/charcoal catalyst. The catalyst was then removed by filtrationand the filtrate treated with concentrated hydrochloric acid (4 ml.-1equivalent) and evaporated in vacuo to a green oil, which was trituratedin diethyl ether/isopropanol to afford a grey tar. Trituration of thelatter in acetonitrile 100 ml.) yielded an olf-white powder (12.71 g.),which was subsequently dissolved in the minimum amount of warm water,the solution then being basified with aqueous sodium carbonate solution.The aqueous phase was decanted from the precipitated green tar and thelatter triturated in turn in diethyl ether and acetone. Successivetriturations in fresh amounts of acetonitrile induced solidification togive a cream-colored product (8.45 g.). Crystallization fromethanol/water alforded a cream-colored solid, M.P.

155-160" C. with decomposition. A silver nitrate test on the productindicated the presence of halide and so it was inferred that the productwas contaminated with the hydrochloride salt. The aqueous ethanolfiltrate was evaporated in vacuo to dryness and the residue combinedwith the crystallized solid, M.P. 155-160 C., and the whole treated withwarm aqueous saturated sodium carbonate solution to convert it to thefree base. Resulting was a fawn powder (6.0 g.) which was crystallizedfrom ethanol to provide fawn crystals (3.7 g.), M.P. 164-166 C. withdecomposition. A final recrystallization from an ethanol/ methanolmixture yielded light fawn crystals (2.85 g.) of DL 1 (4hydroxyphenyD-Z-[Z-(4-{3-methylureido} phenoxy)ethylamino]ethanol, M.P.165-6 C. with decomposition.

Analysis.--Calcd. for C H N O (percent): C, 62.59; H, 6.71; N, 12.17.Found (percent): C, 62.86; H, 6.80; N, 11.88.

EXAMPLE XXXIV Ethyl chloroformate (5.45 g.) was added dropwise over 2-3minutes to a stirred, warm suspension of DL-Z-[N- benzyl 2(4-aminophenoxy)ethylamino]-1-(4-benzyloxyphenyl)ethanol (23.4 g.)(prepared as described in Example XXXIH (A), (B) and (C)) and anhydrouspotassium carbonate (6.9 g.) in ethanol (150 ml.) and the stirredmixture was boiled under reflux for /2 hour. The suspension was thenfiltered hot to remove off-white solid and the filtrate evaporated invacuo to a brown tar (27.0 g.) consisting of crudeDL-2-[N-benzyl-2-(4-ethoxycarbonylaminophenoxy)ethylamino] 1(4-benzyloxyphenyl)ethanol hydrochloride.

The previous crude product (27.0 g.) was dissolved in 1:1 glacial aceticacidzwater (240 ml.) and hydrogenated at 15 p.s.i. and room temperatureover palladium/ charcoal catalyst. Thecatalyst and some accompanyinggrey solid (independently shown to consist in allp robability of themono-O-benzyl compound mainly) were filtered oil, and the yellow aqueousacetic acid filtrate evaporated in vacuo at 40 C. to give a fawn gum,which was triturated in diethyl ether (2X 250 ml.), the resultant fawnsolid then being collected by filtration, dried at C. in vacuo andcrystallized from'ethanol. The product consisted of elf-white crystals(2.25 g.) of DL-2-[2-(4- ethoxycarbonylaminophenoxy) ethylamino] "-"1 (4hy droxyphenyl)ethanol hydrochloride, which melted with decomposition inthe range 187--9- C. to an opaquemelt, the latter decomposing further.with clarification in th'e range 225230 C. i

Analysis.--Calcd. for C H N O -HCl (percent): (3, 57.49; H, 6.35; N,7.06. Found (percent); (3, 57.64; H, 6.06; N, 6.94.

EXAMPLE aqueous formic acid solution (4.3 ml.) was added dropwise over2-3 minutes to a stirred, warm solution'of DL-2-[N-benzyl-2-(4aminophenoxy)ethylamino] 1 (4 benzyloxyphenyDethanol (23.4 g.) (preparedas described in Example XXXI'II (A), (B) and (C) in benzene (150 ml.)and the stirred solution was boiled-under reflux for 1 hour. Evaporationof the solution, which consisted of two liquid layers, in vacuo affordeda brown oil, and this was thendiluted with water (200 ml.) and the pHadjusted to about 6.5 using saturated aqueous sodium carbonate solution.The solution was extracted with chloroform (2X ml.), thechloroform-layers then being separated, dried over anhydrous magnesiumsulfate and evaporated in vacuo to afford a brown tar (26.0 g.), whichconsisted of crude DL-Z-[N-benzyl-Z- (4-formamidophenoxy)ethylamino] 1(4-benzyloxyphenyl)ethanol. r i

The previous crude product (26.0 g.) was dissolved in glacial aceticacid m1.) and hydrogenated at 15 p.s.i. and room temperature over 5%palladium/charcoal catalyst. Evaporation of the filtrate in vacuo at-40"C. from the removal of catalyst yielded a brown tar, which wasazeotroped with benzene (2X 100 ml.). To the resulting brown tar wasadded water ml.) and the pH of the solution, containing suspended whitesolid, was adjusted from about 4.5 to about 9.5, at which point thesolution contained a fawn precipitate. The residual tar was converted tosolid by stirring, the whole solid then being collected by filtrationand recrystallized twice from ethanol to give fawn crystals (6.55 g.) ofDL-1-(4-benzyloxyphenyl) 2 [2-(4-formamidopheuoxy)ethylamino] ethanol,M.P. 151.5-152.5 C.

Analysis.Calcd. for C ll- N 0 (percent): C, 70.91; H, 6.45; N, 6.89.Found (percent): 0, 70.56;H, 6.45; N,

The previous product (4.06 g.) was dissolved in glacial acetic acid (60ml.) and hydrogenated at 15 psi. and room temperature over 10%palladium/ charcoal catalyst. Removal of the catalyst by filtration,followed by evaporation in vacuo of the filtrate afforded a brown oil,to which was added saturated aqueous sodium carbonate solution. Theresultant gum was solidified by trituration in ethanol, and the solidcollected by filtration and crystallized from ethanol to yield off-whitecrystals (2.3 g.) of DL-2-[2-(4-formamidophenoxy)ethylamino ]-1-(4-hydroxyphenyDethanol, M.P. 164-5 C. with decomposition which wasfound from nuclear magnetic resonance spectroscopy to contain about 10%ethanol.

Analysis.-Calcd. for C17H20N204'0-1C2H5OH (percent): C, 64.37; H, 6.47;N, 8.73. Found (P rcent): C, 64.69; H, 6.52; N, 8.92. I

3,816,516 17 18 What is claimed is: LEON ZITVER, Primary Examiner 1.DL-1-(4-hydroxyphenyl)-2-[2-(4-{3-methylureido}phenoxy)ethy1amino]ethano1or a salt thereof with a phar- GLYNN AsslstantExammer maceutically acceptable acid.

5 US. 01. X.R. References f 260281,293.72, 307 R, 326, 326.8, 326.9, 471R, 471 A, UNITED STATES PATENTS 501.19, 553 A, 556 A, 556 AR, 556 c, 558R, 558 s; 3, 5 ,33 10/1962 Moed 260570.6 424272, 320, 321, 322

3,689,524 9/1972 Jack et a1 260553 A

